Synthesis, Cytotoxicity, ADMET and Molecular Docking Studies of Some Quinoline-Pyrimidine Hybrid Compounds: 3-(2-Amino-6-arylpyrimidin-4- yl)-4-hydroxy-1-methylquinolin-2(1H)-ones

Abstract

Aims: Synthesis of 3-(2-amino-6-arylpyrimidin-4-yl)-4-hydroxy-1-methylquinolin-2(1H)-ones and estimation their anticancer activities on HepG2 and KB cancer lines. Background: Many derivatives of quinoline-2-on have been consider to synthesize and evaluate their biological properties by organic chemists due to their various biological effects, including antibacterial, antioxidant, anti-inflammatory, anticancer activities. Quinolinepyrimidine hybrid compounds exhibited various biological activities, such as antituberculosis, antibacterial, anticancer, antifungal, etc. The connection of 4-hydroxyquinoline-2-one with 2-amino-pyrimidine could initiate the new activities. Objective: α,β-Unsaturated ketones of 3-acetyl-4-hydroxy-N-methylquinolin-2-one were prepared. Novel 2-amino-6-aryl-4-(4′-hydroxy-Nmethylquinolin- 2′-on-3′-yl)pyrimidines have been synthesized by reaction of these corresponding α,β-unsaturated ketones with guanidine hydrochloride. Human hepatocellular carcinoma HepG2 and squamous cell carcinoma KB cancer lines were used for screening their cytotoxicity. Method: 3-Acetyl-4-hydroxy-N-methylquinolin-2-one was prepared from N-methylaniline and diethyl malonate. Reaction of (un)substituted benzaldehydes with this 4-hydroxyquinoline-2-one produced corresponding substituted α ,β-unsaturated ketones in the presence of piperidine as catalyst. 2-Amino-6-aryl-4-(4′-hydroxy-N-methylquinolin-2′-on-3′-yl)pyrimidines have been synthesized from these α,β-unsaturated ketones of 3-acetyl-4-hydroxy-N-methylquinolin-2-one by reaction of corresponding α ,β-unsaturated ketones with guanidine hydrochloride. All obtained pyrimidines were screened for anticancer activity using MTT bio-assay method. Result: Seven substituted (E)-4-hydroxy-3-(3-(aryl)acryloyl)-1-methylquinolin-2(1H)-ones were prepared and converted to corresponding substituted 2-amino-6-aryl-4-(4′-hydroxy-N-methylquinolin-2′-on-3′-yl)pyrimidines with yields of 58−74%. All the synthesized pyrimidines were screened for their in vitro anticancer activity against human hepatocellular carcinoma HepG2 and squamous cell carcinoma KB cancer lines. Compounds 6b and 6e had the best activity in the series, with IC50 values equal to 1.32 and 1.33 μM, respectively. ADMET properties showed that compounds 6b, 6e, and 6f possessed the drug-likeness behavior. Cross-docking results indicated that residues GLN778(A), DT8(C), DT9(D), DA12(F), and DG13(F) in the binding pocket as potential ligand binding hot-spot residues for compounds 6b, 6e, and 6f. Conclusion: New substituted 2-amino-6-aryl-4-(4′-hydroxy-N-methylquinolin-2′-on-3′-yl)pyrimidines were obtained and displayed significant inhibition against human hepatocellular carcinoma HepG2 and squamous cell carcinoma KB cancer lines.

Design, synthesis, molecular docking study and molecular dynamics simulation of new coumarin-pyrimidine hybrid compounds having anticancer and antidiabetic activity

“…Reaction yields achieved to 48–78%. As has been mentioned in our previous articles [ 25 , 26 ], several other organic bases can also be used in this condensation reaction, such as trimethylamine and pyridine, and the same yields were obtained with the similar reaction time. On the other hand, strong inorganic bases, such as NaOH and KOH, gave lower yields of target α,β-unsaturated ketones 5a–h due to the ring opening of 2 H -pyran-2-one component of coumarin under these strong base conditions, although these alkaline hydroxides have been successfully applied during the synthesis of other aromatic α,β-unsaturated ketones from aromatic aldehydes and ketones.…”

“…On the other hand, strong inorganic bases, such as NaOH and KOH, gave lower yields of target α,β-unsaturated ketones 5a–h due to the ring opening of 2 H -pyran-2-one component of coumarin under these strong base conditions, although these alkaline hydroxides have been successfully applied during the synthesis of other aromatic α,β-unsaturated ketones from aromatic aldehydes and ketones. This also occurred differently from the similar reaction for synthesis of α,β-unsaturated ketones derived from 3-acetyl-4-hydroxy-1-methylquinolin-2(1 H )-one [ 26 ]. In this reaction, NaOH is used as a base and the reaction goes smoothly because the quinolin-2(1 H )-one ring is not opened under these strong base conditions.…”